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Trimethylaminuria

NORD is very grateful to Elizabeth Shephard, PhD, Professor of Molecular Biology, Department of Structural and Molecular Biology, University College London and Ian Phillips, PhD, Visiting Professor of Molecular Biology, Department of Structural and Molecular Biology, University College London and Emeritus Professor of Molecular Biology, School of Biological and Chemical Sciences, Queen Mary University of London, for assistance in the preparation of this report.

Synonyms of Trimethylaminuria

  • fish odor syndrome
  • stale fish syndrome
  • TMAU

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Trimethylaminuria is a rare disorder in which the body's metabolic processes fail to alter the chemical trimethylamine. Trimethylamine is notable for its unpleasant smell. It is the chemical that gives rotten fish a bad smell. When the normal metabolic process fails, trimethylamine accumulates in the body, and its odor is detected in the person's sweat, urine and breath. The consequences of emitting a foul odor can be socially and psychologically damaging among adolescents and adults. The genetic or primary form of this disorder is transmitted as an autosomal recessive trait.

The metabolic deficiency occurs as a result of a failure in the cell to make a specific protein, in this case the enzyme flavin-containing monooxygenase 3. Enzymes are nature's catalysts and act to speed up biochemical processes. Without this enzyme, foods containing carnitine, choline and/or trimethylamine N-oxide are processed to trimethylamine and no further, causing a strong fishy odor. A secondary form of trimethylaminuria may result from the side effects of treatment with large doses of the amino-acid derivative L-carnitine (levocarnitine) or choline. This secondary form of the disorder is a result of an overload of trimethylamine. In this case, there is not enough of the enzyme to get rid of the excess trimethylamine.

Symptoms

The fish-odor smell is the obvious symptom, otherwise affected individuals appear normal and healthy.

Trimethylamine is normally formed by bacterial action in the intestine on choline (found in foods such as soya, liver, kidneys, wheat germ, brewer's yeast, and egg yolk), or on trimethylamine N-oxide (found in salt water fish). The trimethylamine is then carried to the liver where it is converted to trimethylamine N-oxide, a metabolic product that has no odor.

When secondary trimethylaminuria develops as a result of large oral doses of L-carnitine, choline or lecithin, the symptoms disappear as the dosage is lowered. L-carnitine is used in the treatment of carnitine-deficiency syndromes and is sometimes used by athletes who believe it enhances physical strength. (For more information on this disorder, choose "Carnitine Deficiency Syndromes" as your search words in the Rare Disease Database). Choline is used in the treatment of Huntington disease and Alzheimer disease. Choline and lecithin are present in certain food supplements and 'health' foods.

Causes

Trimethylaminuria is a rare metabolic disorder that is inherited as an autosomal recessive genetic trait (primary), or occurs as the result of treatment with large doses of dietary precursors of the offending chemical (secondary). Symptoms develop when the ability of the liver enzyme (flavin-containing monooxygenase 3) to break down (metabolize) trimethylamine is inhibited. The responsible gene, designated as FMO3, has been tracked to gene map locus 1q24.3.

Although humans have several FMO genes, changes in only one of these, FMO3, causes trimethylaminuria. For reasons that are unclear, many different changes (mutations) of the FMO3 gene exist.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 1q24.3" refers to a region on the long arm of chromosome 1, within the band 24. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.

Affected Populations

Trimethylaminuria is a rare metabolic disorder. More than 100 cases have been reported in the medical literature. Some clinicians believe that the disorder is under-diagnosed since many people with mild symptoms do not seek help. However, some physicians do not recognize the symptoms of trimethylaminuria when a person with body odor seeks a diagnosis.

Related Disorders

N/A

Standard Therapies

Diagnosis
The presence of the rotten-fish odor is indicative, especially in severe cases. However, diagnosis based on smell is unreliable because the odor is often episodic and not everyone can detect the smell of trimethylamine. In addition, on the basis of smell, trimethylaminuria can be difficult to distinguish from other conditions that give rise to an unpleasant body odor. Diagnosis is based on urinary analysis of trimethylamine and trimethylamine N-oxide, which can distinguish between severe and mild cases. Urine analysis after the administration of large doses of trimethylamine can distinguish carriers of the condition from unaffected individuals. Genetic testing is available to distinguish between primary genetic trimethylaminuria, which will result in severe symptoms, from secondary, non-genetic forms of the disorder.

Treatment
In mild cases, symptoms are relieved when foods containing choline and lecithin are restricted. Some severe cases may require the administration of a gut-sterilizing antibiotic such as metronidazole. This treatment reduces the number of intestinal bacteria that break down choline and trimethylamine N-oxide into trimethylamine. In the case of mutations that do not completely abolish FMO3 activity, supplements of riboflavin might help maximize residual enzyme activity. Dietary supplements such as activated charcoal and copper chlorophyllin can bind trimethylamine in the gut and hence reduce the amount available for absorption. The use of slightly acidic soaps and body lotions can convert trimethylamine on the skin into a less volatile form that can be removed by washing. If the disorder is acquired due to excessive doses of L-carnitine, choline or lecithin, symptoms disappear with reduction of dosage.

Genetic counseling may be of benefit for patients and their families.

Investigational Therapies

IInformation on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Trimethylaminuria Resources

NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Treacy EP, Lambert DM. Trimethylaminuria. In: NORD Guide to Rare Disorders. Lippincott, Williams & Wilkins. Philadelphia, PA. 2003:503.

REVIEW ARTICLES
Cashman JR. Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolism. Pharmacogenetics. 2002;30:325-39.

Cashman JR, Camp K, Fakharzadeh SS, et al. Biochemical and clinical aspects of the human flavin-containing monooxygenase for 3 (FMO3) related to trimethylaminuria. Curr Drug Metab. 2003;4:151-70.

Chalmers RA, Bain MD, Michelakakis H, et al. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. J Inherit Metab Dis. 2006;29:162-72.

Hernandez D, Addou S, Lee D, et al. Trimethylaminuria and a human FM03 mutation database. Hum. Mutat. 2003;22:209-13.

MacKay RJ, McEntyre CJ, Henderson C et al. Trimethylaminuria: causes and diagnosis of a socially distressing condition. Clin. Biochem. Rev. 2011;32:33-43.

Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab. Dispos. 2001;29:517-21.

Phillips IR, Shephard EA. Flavin-containing monooxygenases. In: Creighton TE. ed., Wiley Encyclopedia of Molecular Medicine. John Wiley and Sons, New York, NY. 2002:1297-99.

Phillips IR and Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends Pharmacol. Sci. 2008;29:294-301.

Shephard EA, Treacy EP and Phillips IR. Clinical utility gene card for: Trimethylaminuria. Eur. J. Hum. Genet. 2012;20:doi:10.1038/ejhg.2011.214.

Yamazaki H and Shimizu M. Survey of variants of human flavin-containing monooxygenase 3 (FMO3) and their drug oxidation activities. Biochem.Pharmacol. 2013; 85:1588-1593.

JOURNAL ARTICLES
Allerston CK, Vetti, HH, Houge G et al. A novel mutation in the flavin-containing monooxygenase 3 gene (FMO3) of a Norwegian family causes trimethylaminuria. Mol. Genet. Metab. 2009;98:198-202.

Busby MG, Fischer L, da Costa KA et al. Choline- and betaine-defined diets for use in clinical research and for the management of trimethylaminuria. J Am Diet Assoc. 2004;104:1836-45.

Cashman JR, Akerman BR, Forrest SM et al. Population-specific polymorphisms of the human FMO3 gene: significance for detoxication. Drug Metab Dispos. 2000;28:169-73.

Dolphin CT, Janmohamed A, Smith RL, et al. Missense mutation in flavin-containing monooxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17:491-94.

Dolphin CT, Janmohamed A, Smith RL et al. Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FMO3) gene in patients with fish-odour syndrome. Pharnmacogenetics. 2000;10:799-804.

Murphy HC, Dolphin CT, Janmohamed A et al. A novel mutation in the flavin-containing monooxygenase 3 gene, FMO3, that causes fish-odour syndrome: activity of the mutant enzyme assessed by proton NMR spectroscopy. Pharmacogenetcis. 2000;10:439-51.

Shimizu M, Allerston CK, Shephard EA et al. Relationship between flavin-containing mono-oxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population. 2014. Brit. J. Clin. Pharmacol. 2014;77;839-851.

Yamazaki H, Fujieda M, Togashi M et al. Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patients. Life Sci. 2004;74:2739-2747.

INTERNET
FMO3 mutation database: http://databases.lovd.nl/shared/genes/FMO3 (Updated August 15 2013). Accessed August 5, 2014.

Learning About Trimethylaminuria. National Human Genome Research Institute (NHGRI). Updated July 20, 2011. www.genome.gov/11508983 Accessed August 5, 2014.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Trimethylaminuria. Entry No: 602079. Last Edited March 21, 2012. Available at: http://omim.org/entry/602079 Accessed August 5, 2014.

Phillips IR, Shephard EA. Trimethylaminuria. 2007 Oct 8 [Updated 2011 Apr 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1103/ Accessed August 5, 2014.

Treacy EP. Trimethylaminuria and deficiency of favin-containing monooxygenase type 3 (FMO3). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 88.1. Available at http://ommbid.mhmedical.com/content.aspx?bookid=474§ionid=45374077&Resultclick=2 Accessed August 5, 2014.

Trimethylaminuria. Orphanet. Updated May 2009. www.orpha.net/static/GB/trimethylaminuria.html Accessed August 5, 2014.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2014/08/08 00:00:00 GMT+0

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